Comparison of Therapeutic Approaches to Addicted Patients with Central Sleep Apnea.

Background: Nowadays, the most practical approaches used to treat sleep apnea, are Continuous Positive Airway Pressure (CPAP), Bi-level Positive Airway Pressure therapy (BPAP), supplemental O2, servoventilation and/or a combination of these approaches simultaneously. However, each leads to different consequences in opioid related Central Sleep Apnea (CSA) patients. Given the high prevalence of CSA and frequently use of opioids worldwide, it seems that evaluation of the condition in these patients is required to determine their responsiveness to the above mentioned treatments and to choose the most appropriate therapy. Materials and Methods: This longitudinal cross-sectional study included 41 opioid related CSA patients who underwent a step-by-step protocol (including CPAP, CPAP + O2 and BPAP) in which if the patient was nonresponsive to a treatment, the next therapy was applied. If the patient was nonresponsive to all of these approaches, only oxygen was administered. Finally, the collected data were analyzed with SPSS software (ver. 22). Results: Among 41 participants, the responsiveness to CPAP, CPAP+O2 and BPAP were 41.5%, 14.6% and 39%, respectively versus 4.9% nonresponsive patients to all above mentioned therapies. In patients with CSA and opium addiction, the CPAP and BPAP were the most effective treatments. In this group of patients, better response in the presence of higher Apnea–Hypopnea Index (AHI) was observed to BPAP, whereas better response in patients with lower AHI was to CPAP+O2 Conclusion: Accordingly, CPAP and BPAP are successful approaches to treat opioid related CSA patients in various medical conditions including long-run addiction course, concurrent smoking and addiction but it appears that further studies are essential.


INTRODUCTION
The Sleep-Disordered Breathing (SDB) which is generally classified into Obstructive Sleep Apnea (OSA) and Central Sleep Apnea (CSA), has been reported in 6.5 to 9 percent of adults (1).
Despite the lower prevalence of CSA rather than OSA (2), CSA syndromes can be categorized into five subsets: primary (idiopathic) CSA, CSA due to Cheyne-Stokes breathing, CSA due to medical disorder without Cheyne-Stokes breathing, high-altitude periodic breathing and CSA due to drug or substance (3,4).
Given chronic opioid users response to hypercapnia through a depressed ventilation versus their augmented response to hypoxia, the lack of regulation about respiratory chemical reactions may lead to an instable breathing (9,7,10). Hence, some studies have pointed out that sleep apneas could be the cause of mortality induced by over-use of opioids (11,12). However, unfortunately CSA treatment in opioids addicts is rarely investigated (4,13).
Taking into account the concerns about uncontrollable pain and/or increased desire to use opioids, perhaps decreased dosage of opioids cannot be considered as an easy solution to treat (14). Applied treatment options from 2007 so far, including Positive Airway Pressure (PAP) (14), servoventilation (ASV) (15,16), Continuous Positive Airway Pressure (CPAP) (7), BPAP+O2 or CPAP+O2, as a single therapy or step-by-step were used to achieve the desired response (17), although Farney et al. reported no improvement in ataxic breathing and overnight oxygenation in addicted CSA patients using ASV (18).
Thus, given the purity of evidence in literature evaluating the efficacy of available CSA therapies, the lack of similarity of these therapies can be anticipated (19,20).
The contradictory results can be attributed to different definitions of CSA, therapeutic conditions and procedures as well as opioids dosage and medical conditions (4).
Given increasing opioid use worldwide, the role of etiologies as well as concomitants in therapy choice and the lack of a global standard treatment; the current study aimed to evaluate some therapy options in CSA with respect to the histories of concomitants and opioid use in the patients.  Afterwards, providing a CAI of higher than 5 with the oxygen saturation of lower than 93 percent, was considered as nonresponsive case to therapeutic approaches and for the patient, only oxygen was administered and discharged.

MATERIALS AND METHODS
Finally the collected data were analyzed with SPSS (ver. 22). The qualitative data were reported by frequencies (percentage) and the quantitative data were expressed as Mean ± SD. Also, to compare quantitative data of each therapeutic approach with others and the response to treatment two by two, the exact Fisher test was applied and to compare all four therapeutic approaches existing in the study protocol, the Chi-square test was used. Given that the Kolmogorov-Smirnov test indicated the normality of data distribution, for quantitative data and in order to compare the mean variables between responsive and nonresponsive patients to the treatment, we used Independent samples t-test. To compare mean variables of four therapeutic approaches, one-way ANOVA was used and the two by two comparison of therapeutic approaches was made by the post hoc Tukey test. In all analyses, we used a significance level of <0.05.     and 2009, using PAP as a therapeutic approach for chronic opioids users with CSA was successful (15,25). In 2012, two larger studies were conducted to treat CSA as well (17,26).

RESULTS
The results of these two studies suggested success of using  (31,32).
In the literature it has been reported that CPAP without oxygen supplement was ineffective in three patients with a long-run use of opioids and only it can slightly prevent hypoxemia (33).
Also, some studies have pointed out that ASV and BPAP are more expensive than CPAP and in some cases without desired response. Thus, the practical approach can be still using CPAP as the primary therapy, although ASV and BPAP can be applied as alternatives if CPAP failed (9,25,26). Given the various presentations of CSA and its association with opioids use and variations in reactions to opioids (7,34), using a medical approach with paying attention to individual characteristics (e.g. overnight hypoxemia, CSA, awaking reactions, daytime sleepiness/consciousness and so on) can be more rational and safer approach.
Therefore, further RTC studies with larger sample size are recommended to compare basic and clinical outcomes of CPAP and other therapies. Furthermore, lack of longrun patients' follow-up after treatment is one of the limitations of this study. Thus, it is suggested to follow-up patients for a longer period of time in further studies with a similar staged protocol and conduct independent studies to evaluate two-by-two these approaches to provide more appropriate documented results using larger sample size.